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Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

Science, 24 March 2006
Vol. 311, Issue 5768, p. 1770-1773
DOI: 10.1126/science.1123933

Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

  1. Philip T. Liu1,2,*,
  2. Steffen Stenger4,*,
  3. Huiying Li3,
  4. Linda Wenzel4,
  5. Belinda H. Tan1,2,
  6. Stephan R. Krutzik2,
  7. Maria Teresa Ochoa2,
  8. Jürgen Schauber5,
  9. Kent Wu1,
  10. Christoph Meinken4,
  11. Diane L. Kamen6,
  12. Manfred Wagner7,
  13. Robert Bals8,
  14. Andreas Steinmeyer9,
  15. Ulrich Zügel10,
  16. Richard L. Gallo5,
  17. David Eisenberg3,
  18. Martin Hewison11,
  19. Bruce W. Hollis12,
  20. John S. Adams11,
  21. Barry R. Bloom13,
  22. Robert L. Modlin1,2,
  1. 1 Department of Microbiology, Immunology, and Molecular Genetics; University of California at Los Angeles, Los Angeles, CA 90095, USA.
  2. 2 Division of Dermatology, Department of Medicine, David Geffen School of Medicine; University of California at Los Angeles, Los Angeles, CA 90095, USA.
  3. 3 Department of Chemistry and Biological Chemistry, Howard Hughes Medical Institute; and Department of Energy Institute of Genomics and Proteomics, University of California at Los Angeles, Los Angeles, CA 90095, USA.
  4. 4 Institut für Klinische Mikrobiologie, Immunologie, und Hygiene, Universität Erlangen, D-91054 Erlangen, Germany.
  5. 5 Division of Dermatology, University of California at San Diego, and Veterans Affairs San Diego Healthcare Center, San Diego, CA 92161, USA.
  6. 6 Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
  7. 7 Klinikum Nürnberg, Medizinische Klinik 3, D-90340 Nürnberg, Germany.
  8. 8 Pneumologie, Universität Marburg, D-35043 Marburg, Germany.
  9. 9 Medicinal Chemistry, Schering AG, D-13342 Berlin, Germany.
  10. 10 Corporate Research Business Area (CRBA) Dermatology, Schering AG, D-13342 Berlin, Germany.
  11. 11 Department of Medicine, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  12. 12 Departments of Pediatrics, Biochemistry, and Molecular Biology, MUSC, Charleston, SC 29425, USA.
  13. 13 Harvard School of Public Health, Boston, MA 02115, USA.
  1. To whom correspondence should be addressed. E-mail: rmodlin{at}mednet.ucla.edu
  • * These authors contributed equally to this work.

Abstract

In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1–hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D–mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

    • Received for publication 16 December 2005.
    • Accepted for publication 8 February 2006.

    Citation:

    P. T. Liu, S. Stenger, H. Li, L. Wenzel, B. H. Tan, S. R. Krutzik, M. T. Ochoa, J. Schauber, K. Wu, C. Meinken, D. L. Kamen, M. Wagner, R. Bals, A. Steinmeyer, U. Zügel, R. L. Gallo, D. Eisenberg, M. Hewison, B. W. Hollis, J. S. Adams, B. R. Bloom, and R. L. Modlin, Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response. Science 311, 1770-1773 (2006).

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    Journal of the International Association of Providers of AIDS Care (JIAPAC) 11, 305-310 (1 October 2012)

    Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment
    A. K. Coussens, R. J. Wilkinson, Y. Hanifa, V. Nikolayevskyy, P. T. Elkington, K. Islam, P. M. Timms, T. R. Venton, G. H. Bothamley, G. E. Packe et al.
    Proc. Natl. Acad. Sci. USA 109, 15449-15454 (18 September 2012)

    25-Hydroxyvitamin D Response to Cholecalciferol Supplementation in Hemodialysis
    L. A. G. Armas, R. Andukuri, J. Barger-Lux, R. P. Heaney, and R. Lund
    CJASN 7, 1428-1434 (1 September 2012)

    Vitamin D Deficiency in Critically Ill Children
    K. Madden, H. A. Feldman, E. M. Smith, C. M. Gordon, S. M. Keisling, R. M. Sullivan, B. W. Hollis, A. A. Agan, and A. G. Randolph
    Pediatrics 130, 421-428 (1 September 2012)

    Randomized Trial of Vitamin D Supplementation and Risk of Acute Respiratory Infection in Mongolia
    C. A. Camargo, D. Ganmaa, A. L. Frazier, F. F. Kirchberg, J. J. Stuart, K. Kleinman, N. Sumberzul, and J. W. Rich-Edwards
    Pediatrics 130, e561-e567 (1 September 2012)

    The Association of Vitamin D Status With Pediatric Critical Illness
    J. D. McNally, K. Menon, P. Chakraborty, L. Fisher, K. A. Williams, O. Y. Al-Dirbashi, D. R. Doherty, and on behalf of the Canadian Critical Care Trials Gro
    Pediatrics 130, 429-436 (1 September 2012)

    Stem Bromelain-Induced Macrophage Apoptosis and Activation Curtail Mycobacterium tuberculosis Persistence
    S. Mahajan, V. Chandra, S. Dave, R. Nanduri, and P. Gupta
    The Journal of Infectious Disease 206, 366-376 (1 August 2012)

    Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial
    D. Ganmaa, E. Giovannucci, B. R. Bloom, W. Fawzi, W. Burr, D. Batbaatar, N. Sumberzul, M. F. Holick, and W. C. Willett
    Am J Clin Nutr 96, 391-396 (1 August 2012)

    The consequences of chronic kidney disease on bone metabolism and growth in children
    J. Bacchetta, J. Harambat, P. Cochat, I. B. Salusky, and K. Wesseling-Perry
    Nephrol Dial Transplant 27, 3063-3071 (1 August 2012)

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